Processes for the preparation of desa-5-keto steroids

ABSTRACT

This invention is directed to processes for the preparation of desA-androst-9-ene-5-ones and desA-pregn-9-ene-5-ones which comprises the process of subjecting the corresponding 11-hydroxy steroid sequentially to oxidation, pyrolyzation and esterification.

United States Patent [61" Uskokovic et ail.

PROCESSES FOR THE PREPARATION OF DESA-S-KETO STEROIDS Inventors: Milan Radoje Uskokovic, Upper Montclair; Thomas Henry Williams, Passaic, both of NJ.

Assignees Hoffmann-La Roche Inc., Nutley,

Filed: June 17, 1968 Appl. No; 737,278

Related US. Application Data Division of Ser. No. 499,094, Oct. 20, 1965, Pat, No. 3,574,761, Continuation-impart of Ser No. 400,206, Sept. 29, 1964, Pat, No. 3,412,107.

References Cited OTHER PUBLICATIONS Caspi et al., Journal of Organic Chemistry, Vol. 26, pp. 3894-3898. (1961).

Noller, Chemistry of Organic Compounds", p. 198, (1965).

Primary Examiner-Leon Zitver Assistant Examiner- Gerald A. Schwartz Attorney, Agent, or Firm-Samuel IL. Welt; Jon S. Saxe; William H. Epstein [57] ABSTRACT This invention is directed to processes for the preparation of desA-andr0st-9-ene-5-ones and desA-pregn- 9-ene-5-ones which comprises the process of subjecting the corresponding 1 l-hydroxy steroid sequentially, to oxidation, pyrolyzation and esterification.

6 Claims, No Drawings PROCESSES FOR- THE PREPARATION OF DESVA-S-KETO STEROIDS RELATED APPLICATIONS DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel chemical intermediates and processes useful in the preparation of steroids. Natural steroids possess a 9a,l0B-stereochemical configuration. Steroidal compounds possessing the unnatural 9B,l0a-configurationrepresent a pharmaceutically valuable class of compounds which, even though numerous members are known in the art, cannot be ob-' tained by totally classical chemical means. In fact, the

only known methods for obtaining steroids possessing the unnatural 9B,l0a-configuration involve at least one photochemical reaction. Such photochemical reactions involve irradiation with ultraviolet light of strong intensity for long periods of time and, in comparison with purely chemical reactions, are very inefficient and give only small yields.

It is an object of the present invention to provide in- 'termediates and processes which enable the preparation of 913,10a-steroids without the necessity of proceeding through a photochemical reaction. It is also an object of this invention to provide'novel intermediates and processes which will enable the further exploration of steroids having the unnatural 9B,10a-configuration.

It is also an object of this invention to provide novel 9,8, lOa-steroids.

The novel intermediates and processes of this invention are valuable and provide a new synthetic route completely of a classical chemical nature, i.e., involving no photochemical reaction, for converting steroids having the normal configuration into steroidal compounds possessing the unnatural 9B,10a-configuration.

In one aspect, the novel intermediates and processes of this invention enable the preparation of 9B,10asteroids of the androstane series of the formula substituent in the 6- or 7- position selected from 2' the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen. Compounds of formula I are useful as anabolic agents.

Other 9B,10a-androstanes, the preparation of which is enabled by the intermediates and processes of this invention, are of the formulae mo R1 7 ylower alkenyl W R: H

wherein Y and X have the same meaning as above;

R' is selected from the group consisting of hydrogen, lower alkyl, fluoro, hydroxy and lower alkanoyloxy; R is selected from the group consisting of hydrogen and halogen; and] R is selected from the group consisting of hydrogen, lower alkyl, hydroxy and halogen. Compounds of formula IV are useful as progestational agents.

Other 9B,10a-steroids of the l7B-pregnane series, preparable from the novel compounds and process of this invention, are of the formula CHzOH UIII O:

wherein R;,, R Y and X have the same meaning as above; 7 Compounds of formula V are useful as salt-retaining agents, i.e., are useful in the treatment of Addisons disease.

As used herein, the term lower alkyl comprehends both straight and branched chain saturated hydrocarbon groups, such as methyl, ethyl, propyl, isopropyl and the like. Similarly, the term lower alkanoyl com- 7 atom illustrated as follows:

wherein W is lower alkylene, e.g., polymerthylenes such as ethylene, propylene or the like.

With respect to substituents in the 6- and 7-position, preferred compounds are those having hydrogen or lower alkyl in 6- or 7-position, and those having halogen in the 7-position.

In one aspect, this invention comprises a method for the preparation of 9,8,10d-a'ndrostanes of formulae I-III and of 9B,l0a-l 7B-pregnanes of formulae IV-V which comprises the hydrogenation of desA-androst-9-en- -ones or of desA-l7B-pregn-9 en-S-ones to 93,10,8- desA-androstan-S -ones or 9,8,10,8-desA-17B- pregnanS-ones, respectively, followed by condensation with a lower alkyl vinyl ketone with methyl or ethyl vinyl ketone preferred (as well as substitutes therefor such as l-tertiary amino-3-butanone, l-tertiary amino- 3-pentanone'and quaternary ammonium salts thereof), l-Q-butan-3-one, lTQ-butan-3-one lower alkylene ketal, l-Q-butan3-o1,esterified l-Q-butan-3-ol, l-Q- butan-3-ol ether, 1 ,3-dichlorobut-2-ene, l ,3- dichloropent-2-ene, l-pentan-B-one, l-Q-pentan-3-one lower alkylene ketal, l-Q-pentan-3-ol, esterified l-Q- pentan-3-olor l-Q-pentan-3-ol ether, which condensation yields the desired 9B,l0 a-steroids. The symbol Q is bromine, chlorine or iodine, with the former two being preferred. This invention also provides a number of different methods for the preparation of said desA- androst-9-en-5-one or desA-l7B-pregn-9-en-5-one starting materials from natural steroids.

In one embodiment, a steroid of the 3-oxo-androst- 4-ene or 3oxol 7B-pregn-4-ene series is subjected to an oxidative ring opening of the A-ring yielding a 5-oxo- 3,5-seco-A-norandrostan-3-oic acid or a 5-oxo-3,5- seco-A-nor-l7/3-pregnan-3-oic acid, which 3-oic acid can then be converted to a mixture of a IOa-desA- androstan-S-one and a I OB- de A-androStan-S-one or a mixture of a l0a-desA-l7B-pregnan-5-one and a IOB-desA-l7B-pregnan-5-one. The conversion of the 3-oic acid to the desA-compound can be effected either by pyrolysis of a salt of said 3-oic acid orvia the enol lactone, i.e., a 4-oxoandrost-5-en-3-one or a 4-oxo-17B-pregn-5-en-3-one, which upon reaction with a Grignard reagent gives an aldol, which in turn can be converted into the desired desA-compound. The desA- compound can then be converted into the starting material desA-androst-9-en-5-one or desA-.l7,8-pregn-9- en-S-one via a two-step sequence of halogenation and dehydrohalogenation.

In another embodiment of this invention, desA- androst-9-en-5-one or desA-l7B-pregn-9-en-5one starting materials can be prepared from ll-hydroxy steroids of the 3-oxo-androst-4-ene or 3-oxo 17B- pregn-4-ene series. This can be effected in a variety of ways. In one approach, an ll-hydroxy group of a steroid of the 3oxo-androst-4-ene or 3-oxo-17B-pregn- 4-ene series is converted into a leaving group, for example, a sulfonic acid ester or carboxylic acid ester. Oxidative ring opening of the A-ring of the thus formed 1l-( esterified hydroxy)-containing compound yields the corresponding ll-(esterified hydroxy)-5-oxo-3,5- seco-A-norandrostan-3-oic acid or 1 l-( esterified hydroxy)-5-oxo-3 ,5-seco-A-norl 7B-pregnan-3-oic acid which upon pyrolysisof a salt of said 3-oic acid yields the desired desA-androst-9-en-5-one or desA-l7B- pregn-9-en-5-one starting material.

A further approach involves formation of an 11- hydroxy-desA-androstan-S-one or ll-hydroxy-desA- l7B-pregnan-5-one from an ll-hydroxy steroid of the 3-oxo-androst-4-ene or 3-oxo-l7B-pregn-4-ene series via an oxidative ring opening of the A-ring of said ll-hydroxy steroid which yields an ll-hydroxy-S-oxo- A-nor-3,5-secoandrostan-3-oic acid 3,1l-lactone or an 1 1-hydroxy-5-oxo-3,5-secol7B-pregnan-3-oic acid 3,1l-lactone which, in turn is converted into a salt of the corresponding keto acid which salt upon pyrolysis gives the l l-hydroxy-desA-androstan-5-one or l 1- hydroxy-desA-l7B-pregnan-5-one. Esterification of the l l-hydroxy moiety of the so-obtained compound with an acid moiety yields an 1 l-( esterified hydroxy)-desA- androstan-S-one or an 1 1(esterified hydroxy)-desA- l7B-pregnan-5-one which upon elimination of the leaving group i.e., the esterified hydroxy moiety) gives the desired desA-androst-9-en-5-one or desA-l7B-pregn- 9-en-5-one starting material. Though, in the above reaction sequence either 1 lot-OH or 1 lB-OH starting material steroids can be used, it is preferred to use 1 laOl-l starting materials.

As will be appreciated from the above discussion, neither the specific reaction steps nor the reaction sequences of this invention involve any modification of substituents found in the l6-and/or I7-position of the starting material natural steroids. However, in order to obtain unnatural 913,10a-steroids of formulae l-V, it is necessary or desirable to protect certain of the 16- and/or l7-substituents against one or more of the reaction steps involved. It is also convenient to initially prosteps. Said protecting group can then be maintained until the final reaction step or can be split off at some intermediate stage. The protecting groups can be inserted and split off by means know per se. The desirability of having protecting groups present will be further discussed below when the specific reaction steps are discussed in detail. The various substituehts which are susceptible to being protected are exemplified by the l6-hydroxy group in a compound of any of formulas l-V, the l7B-hydroxy group in a compound of any of formulas l-lll, the l7a-hydroxy or -oxo group in a compound of any of formulas lV-V, the 2l-hydroxy group of a compound of formula V or the l7-oxo group of a compound of formula I.

The l7-oxo or 20-oxo group is suitably protected by ketalization, i.e., by reaction with a lower alkanediol, to yield a l7-lower alkylene dioxy or 20.-lower alkylene dioxy compound, i.e., a l7-ketal or a 20-ketal.

The l6-hydroxy, l7a-hydroxy, l7B-hydroxy or 21- hyroxy moieties can be protected by esterification and- /or etherification of the hydroxy group. Any available acid which will form an ester that can subsequently by hydrolyzed to regenerate the hydroxy group is suitable. Exemplary acids useful for this purpose are lower alkanoic acids, e.g., acetic acid, caproic acid, benzoicacid, phosphoric acid and lower alkane dicarboxylic acids, e.g. succinic acid. Also, protection for the 16ahydroxy, l7a-hydroxy, or 2l-hydroxy substituent can be effected by forming the lower alkyl ortho ester thereof, i.e., 16a,17aor 1704, 2l-lower alkyl ortho esters. A suitable ether protecting group is, for example, the tetrahydropyranyl ether. Others are arylmethyl ethers such as, for example, the benzyl, benzhydryl and trityl ethers, or oz-lower alkoxy-lower alkyl ethers, for example, the methoxymethyl, or allylic ethers.

ln compounds containing the dihydroxyacetone side chain at C-l7 (for example, compounds of formula V wherein R is hydroxy), the side chain at C-l7 can be protected by forming the 17,20; 20,2l-bismethylenedioxy group or by forming a l7,2l-acetal or ketal group, or by a l7, 2l-diester. The or and 17,21- diester hinger the 20-ketone group and minimize the possibility of its participating in unwanted side reactions. On the other hand, the l7,20;20,2l-bismethylenedioxy derivatives actually convert the ketone to a non-reactive derivative. When both a loa-hydroxy and l7a-hydroxy substituent are present, these groups can be protected via formation of a l60i,l70t-fltfll or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid hydrolysis.

In compounds wherein there is present neither a 17ahydroxy nor 2 1 -hydroxy substituent but there is present a 2()-oxo group, the 20-oxo group can be protected via reduction to the corresponding carbinol hydroxy) group. Thus, for example, the l7-acetyl side chain can be protected via conversion to a l7( a-hydroxyethyD- carbinol hydroxy) group. Thus, the 17-.oxo group can bereduced to a 17,8-OH, l7a-H moiety, from which, when desired, the l7-oxo moiety can be regenerated by oxidation, as described above. Furthermore, a 20- hydroxy or l7B-hydroxy group, can itself be protected by esterification, for example, with a lower alkanoic acid such as acetic acid, caproic acid, or the like; or by etherification with moieties such as tetrahydropyranyl, benzyl, benzhydryl, trityl, allyl, or the like.

The l6ot-l7aor 1701,21 -acetals and ketals above discussed-can be formed by reacting l6a,l7a-bis-hydroxy or l7ot,2.l-bis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal i.e., a lower alkylene glycol acetal or ketal of a suitable aldehyde or ketone) with the moieties sought to be protected.

Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; di( lower alkyl)ketones, such as acetone diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (lower alkanals), such as cyclopentylcarboxaldehyde and cyclohexylcar'boxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cyclohexylmethyl ethyl ketone; dicycloalkyl ketones, such as dicyclopentyl ketone, dicyclohexyl ketone and cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl pchlorophenyl ketone, cyclophentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolyl ketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyllower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halo-lower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and heptafluorobutanal ethyl hemiacetal; halo-lower alkanones, such as l,1,l-trifluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g., pchlorobenzaldehyde and p-fluorobenzaldehyde), lower alkoxy-benzaldehydes (e.g., o-anisaldehyde), dit lower alkoxy)benzaldehydes (e.g., veratraldehyde), hydroxybenzaldehydes (e.g., salicylaldehyde), lower alkyl benzaldehydes (e.g., m-tolualdehyde and pethylbenzaldehyde), di( lower alkyl)-benzaldehydes e.g., op'dirnethylbenzaldehyde); monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, a'-pheny1propionaldehyde, Bphenylpropionaldehyde, 4-phenylbutyraldehyde, and aromatically-substituted halo, lower alkoxy, hydroxy and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetophenone, mega-trifluoroacetophenone, propiophenone, butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g., p-chloroacetophenone and p-chloropropiophenone); (lower alkoxy) phenyl lower alkyl ketones (e.g., p-

. anisyl methyl ketone); di-( lower allkoxy) phenyl lower alkyl ketones; hydroxy-phenyl lower alkyl ketones; (lower alkyl)phenyl lower alkyl ketones e.g., methyl p-tolyl ketone); dil lower alkyl) phenyl lower alkyl ketones (o,p-xylyl methyl ketone; benzophenone, and mono-or bis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as l-phenyl-3- butanone and l-phenyl-4-pentanone, and aromatically substituted derivatives thereof.

wherein P is individually selected from. the group consisting of hydrogen and lower alkyl; Q is individually selected from the group consisting of lower alkyl and aryl; and P and Q taken together are lower alkylene. The term lower alkylene comprehends polymethylene chains such as tetramethylene and pentamethylene.

In discussing the various starting materials, intermediates and end products of this invention, the various protecting groups discussed above will not necessarily be specifically mentioned, but it should be understood that mention of any substituent comprehends the various protected forms thereof, unless specifically mentioned to the contrary.

In one embodiment of this invention, compounds of formula I through V are prepared from 9B,I0oz-desA- androstan-S-ones or 9B,lOB-desA-pregnan-S-ones of the formula Thus, 98,10a-androstanes of formula I can be prepared from 9/3,]OB-desA-androstan-S-ones of the formula Hac- J H O VII wherein R R R and X have the same meaning as above. Similarly, 9,B,la-and rostanes of formula II can be prepared from 98,1OB-desA-androstan-S-ones of formula VIII and 9B,l0a-androstanes of formula III from 9B,lOB-desA-androstan-S-ones of formula IX.

mo R;

I lower alkynyl 5 H3 C- I H r-Rs H3O 6:0

i "Ra 1 HaC I wherein R';,, R R and X have the same meaning as above.

The conversion of a 9B,10[3-desA-compound of formula VI to a 9B,10a-steroid of formulae I-V (i.e., VII I, VIII II, IX III, X *IV and XI V) is effected by condensing the 9B,lO,B-desA-compound with a compound selected from the group consisting of lower alkyl vinyl ketone (as well as substitutes therefor such as l-tertiary amino-3-butanone, I-tertiary amino- 3-pentanone and quaternary ammonium salts thereof), 1,3-dichlorobut-2-ene, 1,3-dichloropent-2-ene, l-Q- butan-3-one, l-Q-butan-3-one lower alkylene ketal, l- Q-butan-3-ol, l-Q-butan-3-ol ether, esterified I-Q- butan-3-ol, 1-Q-pentan-3-one, 1-Q-pentan-3-one lower alkylene ketal, l-Q-pentan-3-ol, 1Q-pentan-3-ol ether or esterified l-Q-pentan-3-ol. Q is bromo, chloro or iodo, with the former two being preferred. Methyl vinyl ketone and I-tertiary amino-3-butanone are the preferred reagents, and the former is especially preferred. Prior to the condensation it is desirable toprotect the 20-keto group present in compounds of formulae X and XI, then it is not necessary to protect l6a,l7a-or 2l-hydroxy groups which are present, but groups protecting these moieties can be retained through the condensation reaction.

The above indicated substitutes for lower alkyl vinyl ketones are compounds wherein the vinyl moiety is replaced by ,a moiety of the formula wherein each R is a lower alkyl or taken together both Rs are lower alkylene, oxa-lower alkylene or aza lower alkylene. Such moieties are, for example, dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. The quaternary ammonium salts thereof are formed via the utilization of conventional quaternizing agents, for example, lower alkyl or phenyl-lower alkyl (especially benzyl) halides, mesylates or tosylates.

When a lower alkyl vinyl ketone or substitute there for, l-Q-butan-3-one or l-Q-pentan3-one is used as the reaction partner for the condensation, ring closure to ring A (containing a 3-oxo moiety) of the desired 9B,l0a-steroid of formulae l-V occurs simultaneously with the condensation. However, when 1,3- dichlorobut-Z-e'ne, 1,3-dichloropent-2-ene, l-Q-butan- 3-one lower alkylene ketal, l-Q-butan-3-ol, l-Q-butan- 3-01 ether, esterified l-Q-butan-3-ol, l-Q-pentan-B-one lower alkylene ketal, l-Q-petan-B-ol, 1-Q-petan-3-ol ether, or esterified l-Q-pentan-3-ol is used as the reaction partner a subsequent step to generate the 3-oxo moiety is required. When l-Q-butan-3-ol or l-Q- pentan-S-ol is used as the reaction partner, the x0 moiety can be generated by oxidation and for this purpose, it is suitable to use oxidation means knownper se, for example, chromic acid, chromium trioxide in acetic acid or the like. When esterified or etherified l-Q- butan-3-ol or esterified or etherified l-Q-pentan-S-ol is used as the reaction partner, hydrolysis of the esterified or etherified hydroxy group should be effected prior to oxidation. Suitable ester forming moieties are, for example, carboxylic acids, e.g., lower alkanoic acid such as acetic acid, benoic acid, and the like; andhydrolysis of the reaction products obtained by reacting such l-Q- butan-3-ol or l-Q-pentan-3'ol esters is suitably conducted by alkaline hydrolysis, e.g., via the use of an aqueous alkali metal hydroxide such as aqueous sodium hydroxide. Suitable ethers are, for example, lower alkyl ethers, i.e., 3methoxy, 3ethoxy or the like; and these are suitably hydrolyzed by acid hydrolysis, e.g., via the use of an aqueous mineralacid such as hydrochloric acid, sulfuric acid or the like. When a-l-Q- butan-3-one lower alkylene ketal or a l-Q-pentan- 3-one lower alkylene ketal is used as the reaction partner, mild acid hydrolysis of the ketal moiety results in generation of the 3-oxo moiety. Finally, when 1,3- dichloro-but-3-ene or l,3dichloropent-3-ene is used as the reaction partner, the 3-oxo moiety can be generated by treatment with a concentrated mineral acid, preferably a strong acid such as hydrochloric acid or sulfuric acid. It should be noted, that 1,3-dichlorobut- 2-ene and 1,3-dichloropent-2-ene may be used as reaction partners with compounds of formulae X and XI, but not with the l7a-lower alkyl, alkenyl or alkynyl compounds of formulae VIII-IX. As will be apparent, when a reaction partner based on butane i.e., having a four carbon atom skeleton) is utilized a compound of formulae IV wherein Y is hydrogen is obtained. Similarly, when a reaction partner based on penta ne is utilized a compound of formulae l-V wherein Y is methyl is obtained.

It addition to the preparation of compounds of formulae I V from compounds of formulae Vl-Xl by the use of the above mentioned reaction partners, it is also possible by the procedures of this invention to prepare compounds of formulae l-V which, in the A-ring, in addition to containing an unsaturation between the 4- and 5-positions also contain an unsaturation between the l and 2-positions. Such l,4-diene products corresponding to the compounds of formulae l-'V can be prepared from compounds of formulae Vl-Xl by condensation of the latter with a reaction partner selected from the group consisting of ethinyl methyl ketone and ethinyl ethyl ketone (as well as substitutes therefor such as ,B-tertiary amino-vinyl methyl or ethyl ketone, quaternary ammonium salts thereof, and B-lower alkoxy-vinyl methyl or ethyl ketone). Condensation to prepare such a 1,4-diene product corresponding to the compounds of formulae l-V is effected under the same conditions as is the condensation to prepare a compound of formulae l-V. The so-obtained 1,4-clienes are useful in the same way as the correspondingly substituted 4-enecompounds of formulae l-V.

this can be effected via use of a catalyst such as an alkali metal lower alkoxide, for example sodium ethoxide, potassium tbutoxide, sodium t-amylate, or the like, alkali metal hydroxide such as sodium, lithium or potassium hydroxide, a quaternary ammonium hydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide such as benzyl trimethyl ammonium hydroxide, para-toluene sulfonic acid, or the like.

When using a substitute for methyl or ethyl vinyl ketone, or for methyl or ethyl ethinyl ketone, the condensation should be effected under alkaline conditions. As indicated above, among such substitutes are 1-tertiary amino-3-butanone, l-tertiary amino-3-pentanone and B-tertiary amino-vinyl methyl or ethyl ketone. Preferred tertiary amino groups are dilower alkylaminogroups such as dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. Preferred quaternary ammonium salts of such tertiary amino groups are, for example, those formed from lower alkyl halides such as methyl iodide. An exemplary B-lower alkoxy vinyl methyl or ethyl ketone is B-methoxyvinyl ethyl ketone.

One aspect of this invention is the hydrogenation of desA-androstQ-en-S-ones. or desA-pregn-9-en-5-ones XII to R1 s.s.s l.. w

H3O --lower alkenyl i H l5 nac l X XIII XIV wherein R R R and X have the same meaning as above, particularly a compound, in accordance wherein R is hydroxy', lower alkanoyloxy, carboxyloweralkanoloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alloxy-lower alkoxy; R is hydrogen or lower alkyl; R and R taken together are selected from the group consisting of 17/3- OH,l7a-lower alkanoic acid lactone), lower alkylenedioxy and 0x0; R is hydrogen, lower alkyl, hydroxy, lower alkanoyloxy, carboxyloweralk- 6O anoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy, or lower alkoxy-lower alkoxy; and X is a substituent in the 6- or 7position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen. Also, 9B,lOB-desA-pregnan-S-ones of formulae X and XI can be prepared by hydrogenation of desA-pregn-9- en-5-ones of the formulae H30 ---1ower alkynyl T ila 2 5 onrm cmon :0 :0 incl "R5 mo I V NWR': V WR; H n mcn,c-

x v x xv XVI wherein R;,, R R and X have the same meaning as above, particularly a compound, in accordance with this invention, having the formula:

wherein R is hydrogen, fluoro, lower alkyl, hydroxy,

lower alkanoyloxy, carboxylower alkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzyhydryloxy, trityloxy, allyloxy, or lower alkoxylower alkoxy; R is hydrogen, lower alkyl, halogen, hydroxy, lower alkanoyloxy, carboxyloweralkanyoloxy, alkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxy-lower alkoxy; R is hydrogen, halogen, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy, or lower alkoxy-lower alkoxy; X is a substituent in the 6- or 7-position selected from the group-consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen; R is individually hydroxy, loweralkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyanyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxylower alkoxy; and R is individually hydrogen or, taken together with R 0x0 or lower alkylenedioxy; or R and R taken together form a ketal or acetal of a lower alkanal containing at least carbon atoms, of di(loweralkyl)ketone, a cycloalkanone containing from four to six carbon atoms, a (cycloalkyl containing from four to six carbon atoms) lower alkanal, a (cycloalkyl containing from four to six carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 1 l to 13 carbon atoms, a phenyl lower alkanone or benzophenone; or R R and R taken together form a bis-methylenedioxy; or R and R taken together form a ketal or acetal of a lower alkanal containing at least two carbon atoms, a di( lower alkyl)-ketone, a cycloalkanone containing from four to six carbon atoms, a cycloalkyl containing from four to six carbon atoms) lower alkanal, a cycloalkyl containing from four to six carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms, a phenyl lower alkanone, or benzophenone.

Prior to hydrogenation, the C-20 keto group in compounds of formulae XV and XVI or C-l7 keto group in compounds of formula XII should'be protected either by conversion to the corresponding carbino or by ketalization as described above. The hydrogenation can, however, be effected without protecting such keto groups.

Moreover, it should be noted that the hydrogenation, besides inserting a hydrogen atom in each ofthe 9- and IO-positions, can also simultaneously effect hydrogenation of other groups in the molecule. For example, the C-20-keto group can be hydrogenated to the corresponding carbinol or the O1? lower alkenyl group in compounds of formula XIII or the C-17 lower alkynyl group in compounds of formula XIV can be hydrogenated to the corresponding C-I7-lower alkyl compounds. Compounds of formulae VIII and IX can, in turn, be prepared from compounds of formula VII wherein R and R together are oxo via reaction with a lower alkenyl or lower alkynyl Grignard reagent, with prior protection of the S-keto group, for example, by forming S-ketals without concurrent blocking of the I7-keto group. In the same mannercompounds of formulae XIII and XIV can be formed from compounds of formula XII wherein R and R taken together are oxo.

The hydrogenation of desA-androst-9-en-5-ones of formulae XII-XIV and of desAfpregn-9-en-5-ones of formulae XV-XVI is one of the main features of this invention. It is effected by catalytic hydrogenation, suitably using a precious metal catalyst. Suitable precious metal catalysts are palladium, platinum, ruthenium, and rhodium, the latter two being especially preferred. It'is particularly advantageous to use rhodium,

XVII

wherein X is a substitutent in the 6-position selected oic acid or a 5-oxo-3,5-seco-A-norpregnan-3-oic acid for example, rhodium on charcoal I or carbon powder,

carbon black, or the like) or rhodium on alumina. In contrast to what would be expected, it has been found that such a catalytic hydrogenation of a compound of formulae XII-XVI gives a substantial yield of a compound of formulae VI-XI. In fact, it has been found that such catalytic hydrogenation gives a major proportion of a compound of the formulae VI-XI. This catalytic hydrogenation is suitably effected in an inert organic solvent, for example, a lower alkanol such as methanol or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cyclohexane, hexane, or the like. Lower alkanolsare preferred solvents. Moreover, it is suitably conducted in the presence of an acidic or basic catalyst, for example, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or the like, or a mineral acid, for example, a hydrohalic acid, such as hydrochloric acid, or the like, or an organic acid such as lower alkanoic acid, for example, acetic acid. The reaction can be conducted at, above or below room temperature, for example, from about 5 C. to about 100C. However, it is preferably conducted at a temperature between about 0C. and about of theformula XVIII wherein X and Z have the same meaning as above.

The oxidative ring opening of the compound of formula XVII can be performed by a variety of methods. In a preferred embodiment it is effected by ozonolysis. The ozonolysis is suitably carried out in an organic solvent, for example, acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, or the like, or a mixture of two or more of such solvents such as ethyl acetate/acetic acid, ethyl acetate/methylene chloride, or the like. Moreover, the ozonolysis is advantageously conducted at below room temperature. Thus, it is preferably conducted at a temperature between about C. and about 25C. The resulting ozonides can be decomposed by conventional means, for example, by treat ment with water, hydrogen peroxide in water, acetic acid or ethyl acetate, or the like. The oxidative ring opening of a compound or formula XVII to a compound of formula XVIII can also be effected by other oxidation means, for example, by treatment with hydrogen peroxide. It'should be noted that an oxidative ring opening by either ozonolysis or by treatment with hydrogen peroxide, does not require protection of any of the substituents at C-l6 or C-l7. However, as stated above, it may be desirable to protect these substitutents against some subsequent reaction in the total reaction sequence being practiced. On the other hand, the oxidative ring opening can alsobe effected by oxidation with chromium trioxide or via treatment with sodium periodate and potassium permanganate'in potassium carbonate solution and if these oxidation means are used, it is necessary to protect any secondary hydroxy groups which might be present such as a 16,17/3- or 21- hydroxy group; preferably, for the purpose of this reaction, with non-aromatic protecting groups.

Following the oxidative ring opening of the A-ring, the so-obtained 5-oxo-3,5-seco-A-norandrostan-3-oic acid or 5-oxo-3,5-seco-A-norpregnan-3-oic acid of formula XVIII is converted into a mixture of a IOa-desA- androstan-5-one and a IOB-desA-androstan-S-one or a mixture of a IOa-desApregn'an-S-One and a IOB-desA- pregnan-S-one as illustrated below:

alkali metal salt of XVIII wherein in formulae XIX and XX, X' and Z have the same meaning as above.

The compounds of formula XIX are IOa-desA- androstan-5-ones or IOa-desA-pregnan-S-ones, depending on the meaning of Z, and the compounds of formula XX are lOB-desA-androstan-S-ones or 108- desA-pregnan-S-ones. The conversion of a compound of formula XVIII into the compounds of formula XIX and XX is effected by pyrolysis. In effecting the pyrolysis, it is desirable to convert the 3-oic acid of formula XVIII into a corresponding metal salt, for example, an alkali metal salt such as the sodium or lithium salt. This conversion to a metal salt can be effected prior to pyrolysis, e.g., by treating the acid with sodium hydroxide or in situ during the course of the pyrolysis, e.g., by fusing the 3-oic acid with a mixture of sodium acetate and potassium acetate. The pyrolysis can be conducted at atmospheric pressure or in a vacuum. One preferable embodiment is to conduct the pyrolysis in a vacuum, at a temperature from about 200C. to about 350C. in the presence of a proton acceptor, e.g., an alkali metal or alkaline earth metal salt of a weak organic acid, for example, potassium acetate, sodium acetate, sodium phenyl-acetate, sodium bicarbonate, or the like; especially preferred is a vacuum of from about 0.001 to about 0.5 mm. Hg. Accordingly, it is advantageous to conduct the pyrolysis under alkaline conditions, i.e., at a pH greater than 7. The pyrolysis can be effected in solution or by fusion. An especially preferred method of effecting the pyrolysis is by fusion of an alkali metal salt of a weak acid, for example, an organic carboxylic acid such as a lower alkanoic acid or a phenyl-lower alkanoic acid such as phenyl-acetic acid. Another method of effecting the pyrolysis is to heat, preferably at atmospheric pressure, a solution of an alkali metal salt, such as the sodium or lithium salt, of a 3-oic acid of formula XVIII in a basic organic solvent. The basic organic solvent should, of course, be one which is in the liquid state at the temperature at which the pyrolysis is effected. Thus, the pyrolysis can be effected at a temperature up to the boiling point of the basic organic solvent being used. Suitable basic organic solvents are, for example, nitrogen containing organic solvents such as piperidine, pyridine, isoquinoline, quinoline, triethanolamine, or the like. When utilizing this approach using a basic organic solvent it is suitable to heat to temperature between about 200C. and about 300C, and preferably between about 230C. and about 260C. A preferred basic organic solvent for the pyrolysis of a salt of a compound of formula XVIII to compounds of formulae XIX and XX is quinoline. If a basic organic solvent is used which boils substantially below 200C. at atmospheric pressure, it is suitable to conduct the pyrolysis in a sealed tube or an autoclave.

In another aspect, compounds of formula XIX can be prepared from compounds of the formula XIX A wherein X and Z have the same meaning as above.

The compounds of formula XIX can be prepared from compounds of formula XIX A in the same manner that compounds of formula XIX are prepared from compounds of formula XVII, i.e., by oxidative ring opening of the A-ring of a compound of formula XIX A followed by elimination of the residue of the A-ring, to yield a compound of formula XIX. The oxidative ring opening of the compound of XIX A can be performed by ozonolysis as described above for the conversion of a compound of formula XVII to a compound of formula XVIII. Such ozonolysis of a compound of formula XIX A yields a compound of the formula XIX 13 wherein X and Z have the same meaning as above,

and A is carboxy or formyl.

deformylation yields mainly a compound of formula XIX, but also a minor yield of the corresponding 10B- isomer of formula XX.

Compounds of formula XIX can also be formed from a compound of formula XVIII via the formation of an enol-lactone of a compound of formula XVIII, i.e., via the formation of a 4-oxo-androst-5-en-3-one or a 4-oxo-pregn-5-en-3-one of the formula:

pound of formula XVIII yields both the wherein X and Z have the same meaning as above, which can then be reacted with a Grignard reagent,

such as phenyl magnesium bromide or phenyl lithium,

to form the resulting aldol of, for example, the formula Q X @0115 OH XXII compounds of formula XX and the IOa-compounds of formula XIX, and though either of these isomers can be used in the subsequent halogenation and dehydrohalogenation steps of this reaction sequence, it is sometimes preferable to convert the IOB-compound of formula XX into the corresponding IOa-compound of formula XIX. This conversion can be effected by treating a IOB-desA-androstan-S-one or IOB-desA-pregnam S-one of formula XX with any base capable of producing a carbanion; for example, it is suitable to use an alkali metal lower alkoxide in an organic solvent such as a lower alkanol, for example, sodium ethoxide in an ethanol solution or sodium methoxide in a methanol solution.

The above'discussed conversion via the alkali metal salt and pyrolysis of compounds of formula XVIII to compounds of formulas XIX and XX can be effected without protection of any of the substituents which might be present at C-l6 or C-17. However, if it is desired for either preceding or succeeding reaction steps of the total reaction sequence, the conversion of a compound of formula XVIII to compounds of formulas XIX and XX can be effected with protecting groups present on substituents in the (3-16 or C-l7 position.

As stated above, the lOa-desA-androstan-S-ones or ll-dSA-PfgflfiH-5OHBS of formula XIX or the 103- desA-androstan-S-ones of lOB-desA-pregnan-S-ones of formula XX can be converted via a two-step sequence of halogenation and dehydrohalogenation into the desired starting material desA-androst-9-en-5-one or desA-pregn-9-en-5-one of formulas XII, XV, and XVI.

In a preferred embodiment a 10a-desA-androstan- -one or a IOB-desA-pregnan-S-one of formula XIX is subjected to the two-step sequence of halogenation and dehydrohalogenation. Halogenation of a compound of formula XIX or a compound of formula'XX yields a mixture of corresponding halogenated compounds ineluding one of the formula XXIII wherein X and Z have the same meaning as above, and Hal is a halogen atom( preferably Br or Cl). Dehydrohalogenation of a compound of formula XXIII then yields a desired starting material of formulas XII, XV and XVI. Keto groups except for the S-keto group, may require protection prior to the halogenation. In the case of compounds of formulas XlIX and XX containing the C-l7 dihydroxyacetone side chain, represented in formula V wherein R is hydroxy, this protection can be effected by formation of the 17a,20;20,21-bismethylenedioxy derivative. In other cases wherein a C-17 0x0 or 020 0x0 group is present, protection can be effected by reduction to the corresponding carbinol either directly prior to the halogenation step or prior to some other step in the reaction sequence leading to the compounds of formulas XIX and XX.

The halogenation can be effected with halogenating agents such as bromine, sulfuryl chloride, or the like. Bromination is especially preferred. The bromination is suitably effected by treatment with bromine at room temperature or below, preferably at ice temperature or below. Suitably it is conducted in an organic medium; for example, an organic acid such as acetic acid; an ether such as an anhydrous ether, dioxane, tetrahydrofuran; a chlorinated organic solvent such as methylene chloride, chloroform, carbon tetrachloride; or the like; with the addition of hydrogen bromide as a catalyst. When effecting halogenation with sulfuryl chloride, it is suitable to use the same type of organic medium as when brominating; and suitable catalysts are, for example, acetic acid, benzoyl peroxide, or the like.

The subsequent dehydrohalogenation of a compound of formula XXIII is preferably conducted under mild dehydrohalogenating conditions; for example, by the use of an alkali metal carbonate t e.g., lithium carbon ate) or an alkali metal halogenide (e.g., a lithium halide) in an organic solvent such as a dilower alkylformamide, or with an organic base such as collidine,

pyridine, or the like. The dehydrohalogenation is advantageously conducted at slightly elevated temperatures, for example, from about 50C. to about 150C, preferably from about C. to about C.

Separation of the desired product desA-androst-9- en-S-one or desA-pregn-9-en-5-one of formulas XII, XV and XVI can be effected by conventional means. As indicated above the halogenation procedure may result in halogenated by-products in addition to the desired intermediate of formula XXIII. Accordingly, the separation is preferably effected after first subjecting the reaction mixture to dehalogenating conditions in order to dehalogenate the halogenated by-products formed by the halogenation procedure, but not dehalogenated by the dehydrohalogenation. Following such dehalogenation the reaction mixture can then easily be separated by conventional means, for example,

19 by column chromatography, to yield the desired compound of formulas XII, XV, XVI. An examplary dehalogenation means is treatment with zinc and sodium acetate in an acetic acid solution at an elevated temperature, for example, about 80C.

In the case of compounds of formulas XIX or XX which contain a halogen atom on a carbon atom directly adjacent to a keto group, it is preferable to protect such a halogen atom against dehalogenation prior to subjecting the compound of formulas XIX or XX to the two step sequence of halogenation and dehydrohalogenation of this embodiment. Such a grouping, containing a halogen atom on a carbon atom directly adjacent to a keto group, is illustrated in a compound of formulas IV or V wherein R or R is halogen. Thus, if 1001- or IOB-desA-pregnan-S-one of formulas XIX or XX containing a l7aor 2l-halo substituent is to be subjected to the halogenation-dehydrohalogenation sequence it is desirable to first effect protection of the 1701- or 2l-halo substituent. This protection can be effected, for example, by ketalization of the -oxo group.

As stated above, the desired =desA-androst-9-en- 5-ones or desA-pregn-9-en-5-ones starting materials can also be prepared from steroids of the 3-oxoandrost-4-ene or 3-oxo-l7B-pregn-4-ene series containing an 1 l-hydroxy substituent. In one embodiment an ll-hydroxy steroid of the formula XXIV V,

wherein X and Z have the same meaning as above, particularly a compound, in accordance with this invention, having the formula:

wherein R -is hydrogen, fluoro, lower alkyl, hydroxy,

lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy, or lower alkoxy-lower alkoxy; R is hydrogen, lower alkyl, halogen, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy, or lower alkoxy-lower alkoxy; R is hydrogen, halogen, hydroxy, lower alkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy, or lower alkoxy-lower alkoxy; X is a substituent in the 6- or 7-position selected from the group consisting of hy drogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen; R is individually hydroxy, loweralkanoyloxy, carboxyloweralkanoyloxy, benzoyloxy, tetrahydropyranyloxy, benzyloxy, benzhydryloxy, trityloxy, allyloxy or lower alkoxylower alkoxy; and R is individually hydrogen or, taken together with R 0x0 or lower alkylenedioxy; or R and R taken together form a ketal or acetal of a lower alkanal containing at least two carbon atoms, of di( loweralkyl)ketone, a cycloalkanone containing from four to six carbon atoms, a (cycloalkyl containing from four to six carbon atoms) lower alkanal, a cycloalkyl containing from four to six carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms, a phenyl lower alkanone or benzophenone; or R R and R taken together form a bis-methylenedioxy; or R and R taken together form a ketal or acetal of a lower alkanal containing at least two carbon atoms, a di( lower alkyl)-ketone, a cycloalkanone containing from four to six carbon atoms, a cycloalkyl containing from four to six carbon atoms) lower alkanal, a (cycloalkyl containing from four to six carbon atoms) lower alkanone, a dicycloalkyl ketone containing from 11 to 13 carbon atoms, a phenyl lower alkanone, or benzophenone, is reacted with an acid or a reactive derivative thereof to form a leaving group in the ll-position. By reactive derivative is meant, for example, a halide, e.g., a chloride, an anhydride, or the like. Though either 1 1,8- or lla-hydroxy starting materials can be used, it is preferable to utilize a-hydroxy com-- pounds of formula XXIV as starting materials. Prior to the esterification reaction, it is preferable to protect hydroxy groups present in the G16, C-17, or 021 position. Suitable acids for the esterification of the ll-hydroxy group, which can be used to form a leaving group in the l l-position are inorganic acids such as phosphoric acid, organic carboxylic acids such as anthraquinon e B-carboxylic acid or organic sulfonic acids, for example, toluene-sulfonic acids, especially p-toluene sulfonic acid, lower alkylsulfonic acids such as methane- XXV wherein X and Z have the same meaning as above,

and LO represents the leaving group.

In the next step of this reaction sequence, the soformed ll-(esterified hydroxy)-c ompound of formula XXV is subjected to an oxidative ring opening of the A-ring to yield the corresponding l l-(esterified hydrotion yields a A -seco acid of the: formula xy)-5-oxo-3,5seco-A-norandrostan-3-oic acid or 1 1- (esterified hydroxy)-5-oxo-3,5-seco-A-norpregnan-3- oic acid of the formula Inc X XXVI wherein X, Z and LO have the same meaning as above. The oxidative ring opening of the A-ring of a compound of formula XXV to a compound of formula XXVI can be effected by ozonolysis as described above for the oxidative ring opening of the A-ring of a compound of formula XVII to a compound of formula XVIII. Pyrolysis of the so-formed compound of formula XXVI under the conditions described above for the pyrolysis of a compound of formula XVIII to compounds of the formulas XIX and XX directly yields the desired dcsA-androst-J-en-S-one or desA-pregn-9-en-5-one of formulas XII, XV, XVI. Thus, pyrolysis ofa compound of formula XXVI directly results in elimination of the leaving group in the l l'position as well as asplitting off of the residue of ring A attached to the lO-position. This procedure of starting from an I l-hydroxy steroid (preferably lla-hydroxy) of formula XXIV and proceeding through intermediates of formulas XXV and XXVI to compounds of formulas XII, XV, XVI, represents a particularly elegant procedure for preparing the latter compounds. An especially preferred method of effecting the pyrolysis of a salt of a 3-oic acidof for mula XXVI is'the method described above wherein the salt of the 3-oic acid is heated in a liquid basic organic solvent. Especially preferred solvents for the pyrolysis of a salt of a compound of formula XXVI are triethanolamine and quinoline.

As indicated in the foregoing paragraph the pyrolysis of a salt of a compound of formula XXVI involves two separate chemical attacks; one being the elimination of the l l-leaving group and the other being the splitting off of the A-ring residue. Instead of effecting these two attacks simultaneously, as described above, it is also possible to effect them sequentially by just prior to formation of the salt, effecting elimination of the leaving group of the compound offormula XXVI. This elimina- XXVIA wherein X and Z have the same meaning as above. The elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solventPreferably, it is effected by heating, i.e., at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of formula XXVI with either an inorganic or organic acid or base results in the formation of the de' sired compound of formula XXVIA. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g., a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkylformamides, e.g., dimethylformamide, lower alkanoic acids, e.g., acetic acid, or the like. When a proton ac cepting solvent, such as dimethylformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e., if the solvent is basic then the elimination can be conducted without the addition of a separate basic material. Similarly, if the solvent is acidic, then the elimination can be conducted without the addition of a separate acidic material.

After the elimination is effected. the A -seco acid product of formula XXVIA can then be converted to a salt, for example, an alkali metal salt, and the soformed salt pyrolyzed according to the conditions described above for the pyrolysis of a compound of formula XXVI to compounds of formulas XII, XV and XVI.

After the above-described l l-leaving group elimination and A-ring residuesplitting, conducted either simultaneously or sequentially, the desired desA-Q-en- 5-one compounds of formulas XII, XV and XVI can be isolated by conventional means. However, it has been found particularly suitable with compounds of formulas XV and XVI to isolate by forming the disemicarbazone of the pyrolysis product and then regenerating therefrom the desired 5,20-dione of formulas XV or XVI, or if the 20-oxo group has been protected, for example, by reduction to a ZO-hydroxy moiety, by forming the semicarbazone at the 5-position and then regenerating therefrom the desired S-one compound.

In yet another embodiment of this invention starting material I l-hydroxy steroids of formula XXIV can be directly subjected to an oxidative ring opening of the A-ring by'ozonolysis or treatment with hydroxide peroxide, as described above for the oxidative ring opening of the A-ring of a compound of formula XVII to a compound of formula XVIII. This oxidative ring opening of the A-ring of a compound of formula XXIV yields an ll-hydroxy--oxo-3,S-seco-A-norandrostan- 5-oic acid 3,ll-lactone or an ll-hydroxy-3-oxo-3,5- seco-A-norpregnan-3-oic acid 3,1 l-lactone of the formula XXVII wherein X and Z have the same meaning as above. Treatment of the 3,1 l-lactone of formula XXVII with an alkali metal hydroxide such as sodium hydroxide gives the salt of the same keto acid. Without isolation, this salt can then be subjected to pyrolysis yielding a mixture of an I l-hydroxyl Oct-desA-androstan-S-one and an ll-hydroxy-IOB-desA-androstan-S-one or a mixture of an ll-hydroxy-lOB-desAmregnan-S-one and an ll-hydroxy-IOB-desA-pregnan-S-one, as illustrated below:

XXVII alkali metal salt 11 C H3O HOW HO/vw I H D H z r 1 i HaC i I Ha H I H i H H O O--\ XXVIII XXIX wherein in formulas XXVIII and XXIX, X and Z have the same meaning as above.

This pyrolysis of an alkali metal salt derived from a compound of formula XXVII can be effected under the same conditions as described above for the pyrolysis of a compound of formula XVIII to compounds of the formulae XIX an XX. Though either the lOB-compound of formula XXVIII or the lOu-compound of formula XXIX can be subjected to the subsequent steps of this reaction sequence, it is suitable to utilize the 108- compound of formula XXVIII. Conversion of the 100:-

same acids or acid derivatives and in the same manner as described above for the esterification of a compound of formula XXIV to a compound of formula XXV. As

XXX

wherein X, Z and LO have the same meanings as above.

The leaving group can then be eliminated from the l 1- position of a compound of formula XXX resulting in a direct formation of a desA-androst-9-en-5-one or a desA-pregn-9-en-5-one of formulae XII, XV, VVI. This elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e., at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of formula XXX with either an inorganic or organic base results in the formation of .the desired compound of formulae XII, XV, XVI. Preferably a weak base is used, for example, a salt of a 'carboxylic acid (e.g., a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g., dimethyl formamide, lower alkanoic acids, e.g., acetic acid, or the like. When a proton accepting solvent, such as dimethyl formamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e., if the solvent is basic then the elimination can be conducted without the addition of a separate basic material.

In another aspect, compounds of Formula XXX can be prepared from compounds of the formula XXXA wherein X, Z and LO have the same meanings as above.

The compounds of formula XXXA can be prepared from corresponding 1 l-hydroxy compounds by esterification as described above for the preparation of compounds of formula XXV from-compounds of formula XXIV. The compounds of formula XXX can be prepared from compounds of formula XXXA in the same manner that compounds of formula XXX are prepared from compounds of formula XXV, i.e., by oxidative ring opening of the A-ring of a compound of formula 25 XXXA followed by elimination of the residue of the A- ring to yield a compound of formula XXX. The oxida- XXXB wherein X, Z and LO have the same meaning as above.

A compound of formula XXXB can then be converted to a compound of formula XXX. This removal of the residue of the A-ring, i.e., decarboxylation, can be effected as described above for the conversion of a compound of formula XIXB to a compound of formula XIX.

The compounds of formulae I-V preparable by the methods of this invention are not only pharmaceutically useful compounds as described above, but also are themselves useful as intermediates for other 9,8,10a-steroids; for example, compounds wherein X is hydrogen or lower alkyl can be modified so as to introduce unsaturation between C-6 and C-7. This can be effected by dehydrogenation means, for example, by halogenation followed by dehydrohalogenation or by means of 2,3-dichloro-5,-dicyanobenzoquinone, according to known methods. Thus, for example, a 9B,l0a-progesterone of formula IV wherein X is hydrogen or lower alkyl can be converted to a 93,100:- pregna-4,6-dien-3,ZO-dione.

A further embodiment of this invention comprises 11,0 ROMA I n I J 4, 0=U

XXXI wherein X and Z have the same meaning as above, and E0 is an esterified hydroxy group as described above in this paragraph, yields an I l -esterified hydroxy-desA-9,8,l0,8-

androstan-S-one or 11 -esterified hydroxy-desA- 9B,l0B-pregnan-5-one, of the formula XXXII wherein X, Z and E0 have the same meaning as above.

This hydrogenation can be conducted in-the same manner as described above for the hydrogenation of a compound of formulae XII-XVI to a compound of formulae VII, X, XI. Also, compounds of formula XXXll containing a 17-oxo moietycan be converted to a corresponding compound containing a 17B-hyd'roxy, 17ozlower alkenyl or lower alkynyl moiety by the methods described above. Also, compounds of formula XXXII can be hydrolyzed to yield corresponding Il-hydroxy compounds of formula XXXII, i.e., wherein E0 is hydroxy.

Condensation of the 'so-obtained compound of formula XXXII or the corresponding 17,8-hydroxy, 170:-

the preparation of 9B,lOor-steroids of formulae l-V containing an I l-hydroxy substituent. This can be effected by utilizing an I l-hydroxy- IOa-desA-andrQStan-S-Qne or 1 l-hydroxy-l0a'-desA- pregnan-S-one of formula XXIX or an ll-hydroxy- IOB-desA-androstan-S-one or ,1 l-hydroxyl OB-desA-pregnan-S-one of formula XXVIII as the starting materials. It is preferred in this embodiment to use the lOB-isomers of formula XXVIII as starting materials. As a first step in this the 11- hydroxy group of the compound of formulae XXVIII or XXIX should be protected. This is suitably effected by esterification, preferably with a carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, or the like. Conversion of the sobtained l 1- esterified hydroxy compound then yields an 11- (esterified hydroxy)-desA-androst-9-en-5-one (i.e., a

compound of formula XII containing an ll-esterified hydroxy moiety) or an ll-esterified hydroxy-desA- pregn-9-en-5-one (i.e., a compound .of formulae XV-XVI containing an lla-esterified hydroxy moiety). This conversion can be effected by halogenation followed by dehydrohalogenation, as described above for the conversion of a compound of formulae XIX or XX to a compound of formulae XII, XV or XVI. Catalytic hydrogenation of the so-obtained compound of the formula lower alkenyl or lower alkynyl compound (i.e., a compound of formula VI containing a free or I l-esterified hydroxy group) then yields the desired end-product 95, IOa-steroid of formulae l-V containing an ll-hydroxy group. Such condensation can be effected as described above for the preparation of a compound of formulae I-V from a compound of formulae VI-XI. The soobtained 913,10oz-steroids containing an ll-esterified hydroxy group can be hydrolyzed to the corresponding compounds containing an ll-hydroxy group, which latter compounds are themselves useful as intermediates, for example, the l l-hydroxy group can be oxidized by methods known per se to yield corresponding ll-oxo steroids analogous to compounds of formulas I-V.

The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.kg., capsules, tablets, suspensions, solutions, or the li e.

The following examples are illustrative but not limitative of this invention. All temperatures are in degrees Centigrade. The Florisil adsorbent used infra is a synthetic magnesia-silica gel available from the Floridin Company, P. O. Box 989, Tallahassee, Fla. (cf. p. I590, Merck Index, 7th Edition, 1960). IO0-200 mesh material was used. The moiety designated by tetrahydropyranyloxy is tetrahydro-Z-pyranyloxy. When it is stated that a procedure is effected in the cold, it should be understood that it is commenced at C. Throughout this application when .compounds of the pregnane series are referred to it should be understood that it is compounds of the 17B-pregnane series that are being referred to, unless specifically indicated to the contrary, and whether or not the compound of the pregnane series is specifically indicated as of the 17B-series.

EXAMPLE 1 A solution of 3.2 g. of 17a-ethyltestosterone in 50 ml. methylene chloride and 25 ml. ethyl acetate was ozonized at -70 (acetone-dry ice bath) until the solution was blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The syrupy residue was then dissolved in 100 ml. of glacial acetic acid, and after addition of ml. of 30 percent hydrogen peroxide, left for 24 hours at 0-5. Following this time, it was evaporated to dryness, dissolved in 1,500 ml. ether, and extracted with 2N sodium carbonate solution. The alkaline extract was poured in ice Cold h qch o is. itssw tantstys a liue,17g-

ethy l-1 7B hydroxy-5-oxo-3,5-seco-A-norandrostan-3- oic acid was filtered, washed with water and dried. Upon being recrystallized from acetone, it melted at .196-197.

EXAMPLE 2 I A solution of 1.5 g. of l7a-ethy1-l7B-hydroxy-5-oxo- 3,5-seco-A-norandrostan-3-oic acid in 100 ml. of methanol was titrated with 2N sodium methoxide to the red dish color of phenolphthaleine, and then evaporated to dryness in vacuo, giving as the residue, the sodium salt of 17a-ethyl-17B-hydroxy- 5-oxo-3,5-seco-A-norandrostan-3-oic acid. 5 g. of sodiumphenylacetate was added to the residue, and the mixture pyrolyzed in vacuo 0.1 mm) at 285295, for 2.5 hours. The sublimate was dissolved in acetone, filtered and the filtrate concentrated in vacuo. The resultant syrupy residue was chromatographed on a 60 g. Florisil (adsorbent) column. The fractions eluted with benzene and 0.5 percent ethylacetate in benzene were combined and gave 17a-ethyl-l7B-hydroxy-IOa-desA- androstan-S-one, m.p. 94-95 after recrystallization from petroluem ether. The fractions eluted with 2 percent and 5 percent ethylacetate in benzene were combined v and gave 17a-ethyl-17B-hydroxy-10B-desA- androstan-5-one, m.p. l85185.5, after two recrystallizations from petroluem ether.

EXAMPLE 2a:

To a solution of 100 mg. of 17a-ethyl-l7B-hydroxy- 1OB-desA-androstan-5-one in ml. of absolute ethanol was added one equivalent of sodium ethoxide dissolved in 5 ml. of absolute ethanol. This reaction mixture was maintained at room temperature overnight, then acidified with glacial acetic acid, poured in water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thin layer chromatog raphy showed the product to be l7a-ethyl-l7B- hydroxy-10a-desA-androstan-S-one. It was obtained crystalline from petroleum ether-ether and melted at 8995.

28 EXAMPLE 3 1.13 g. of l7a-ethyl-17B-hydroxy-10a-desA- androstan-5one was dissolved in 120 ml. of anhydrous ether (or 1.13 g. of l'OB-isomer was dissolved in 300 ml. of anhydrous ether), and after cooling in a salt-ice bath, several drops of 30 percent hydrobromic acid in acetic acid were added. This was followed by the dropwise ad dition during 5 minutes of 0.684 g. of bromine dissolved in 2 ml. of acetic acid. This addition was synchronized with the decoloration rate of the reaction mixture. Immediately after this, 5 ml. of a saturated solution of sodium bisulfite and 5 ml. of 2N sodium carbonate solution were added. The mixture was then transferred into a separatory funnel, 500 ml. of ether added, shaken and separated. The ether part was washed with water, dried and evaporated. The resultant bromides were dissolved in 100 ml. of dimethylformamide, and after addition of 3 g. of lithium carbonate, the solution was heated at 100 for 45 minutes. After cooling, it was poured into one liter of ether, washed with water, 1N hydrochloric acid, 2N sodium carbonate, water, dried and evaporated. The residue was dissolved in 40 ml. of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. of zinc powder added, and the soformed mixture heated 10 minutes at It was then poured into one liter of ethylacetate and the resultant solution washed with saturated sodium bicarbonate, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column. The fraction with benzene and /2 percent ethylacetate in benzene gave regenerated starting material. Fractions with 1 and 2 percent ethylacetate in benzene gave 17aethyl-17B-hydroxy-desA-androst-9-en5-one, which after sublimation 140 and 0.1 mm. Hg vacuum), was obtained as a glass. [111 36.6 0 1, CHCl EXAMPLE 4 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of percent ethanol and 5.25 ml. of 2N sodium hydroxide solution was pre-reduced, (i.e., hydrogenated at room temperature and atmospheric pressure). To this was added a solution of 262 mg. of l7a-ethyl-l7B-hydroxydesA-androst-9en-5-one in 15 ml. of 95 percent ethanol, and the mixture then hydrogenated at atmospheric pressure and room temperature. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate evaporated in vacuo. Glacial acetic acid 1 ml.) was added to the residue, which was then dissolved in 1 liter of ether. The cloudy solution which resulted was washed with 2N Na CO solution, then with water, dried and evaporated to dryness in vacuo.

The reaction was repeated 3 more times, and the combined products chromatographed on a Florisil adsorbent) column. The eluates with 1 percent ethyl acetate in benzene gave first crystalline fractions, which were followed by non-crystalline fractions. The noncrystalline fractions were dissolved in ml. of methylene chloride, and after the addition of 2.5 ml. of 2 percent CrO in 90 percent acetic acid, stirred overnight. The excess of chromic acid was removed by washing the methylene chloride solution with 10 ml. of 10 percent sodium hydrogen sulfite solution, followed by washing with 2N Na CO solution and then with water. It was then dried and evaporated in vacuo. The residue was dissolved in 50 ml. of anhydrous ethanol'containing 172 mg. of sodium ethoxide, and left overnight. The next day, after addition of 0.5 ml. of glacial acetic acid, the solution was evaporated in vacuo, and the residue was taken up in 1 liter of ether. The ether solution was washed with 2N Na CO solution, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column and gave crystalline 17a-ethyll 7B-hydroxydesA-9B,IOB-androstan-S-one identical (by thin layer chromatography) with the crystalline material obtained in the first chromatographic separation. After two recrystallizations from ether, it melted at l42-l44; [041 1l.65 [methonaL c 1.245 percent].

EXAMPLE 5 To a solution of 132 mg. of 17a-ethyl-l7B-hydroxydesA-9B,10B-androstan-5-one in 12.5 ml. of absolute ethanol containing 34 mg. of sodium ethoxide, 0.15 ml. of freshly distilled methylvinyl ketone was added. The

reaction mixture was then refluxed for 2 hours in a nitrogenatmosphere. After cooling the reaction mixture, 0.1 ml. of glacial acetic acid was added thereto and the resulting mixture was then poured into 1 liter of ether. The resultant ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was chromatographed on fluorescent silica-gel plates, with the solvent system, 60 percent ethyl acetate 40 percent heptane. The fluorescent part of the layers was extracted with ethyl acetate. The residue obtained after evaporation of ethyl acetate was first crystallized from ether-petroleum ether, then a second time from pure ether, yielding l7a-ethyl-. 9B,l0a-testosterone, m.p. l31l35.

EXAMPLE 6 A solution of 6.4 g. of lla-hydroxy-progesterone in 100 ml. of ethylacetate and 50 ml. of methylene chloride was treated with ozone at -70 until the solution became blue in color. Oxygen was then passed through and the solution evaporated at room temperature in vacuo. The so-obtained syrupy residue was dissolved in 100 ml. of glacial acetic acid, and after the addition of 5 ml. of percent hydrogen peroxide, left for 24 hours at 2 (in an ice box). The solution was then evaporated in vacuo, and the residuetriturated with ether yielding crystals. Recrystallization from acetone yielded llahydroxy3,S-seco-A-nor-pregnane-S,20-dione-3-oic acid 3,1 llactone, m.p. 253-256. [041 193.3 (c=l, in chloroform),

EXAMPLE 7 A methanolic solution of 7.5 g. of l la-hydroxy-3,5- seco-A-nor-pregnane-S,20-dione-3-oic acid 3,11- lactone was treated with one equivalent of ION sodium hydroxide solution and then evaporated to dryness. Sodium phenylacetate (26 g.) was added to the soobtained sodium salt and the mixture pyrolyzed at 295 for 2 hours in vacuo. The crude sublimate was chromatographed on a silica-gel column and eluted with 10 percent ethylacetate in benzene. The amorphous solid lla-hydroxy-lOa-desA-pregnane-S,20-dione was first eluted from the column. IR-spectrum in chloroform: 3620 and 3600 cm (-OH);. 1706 cm (carbonyl group). NMR-spectrum in deuterochloroform: a doublet for l0a-CH at 73.5 and 80.5 c.p.s. downfield from 'TMS at Mc/sec. Further elution of the column with 10 percent ethylacetate in benzene yielded crystalline lla-hydroxy-l0B-desA-pregnane-5,20-dione which was recrystallized from methylene chloridepetroluem ether, m.p. l50l52; [01],, 84.0 (c=0.5 in absolute ethanol).

EXAMPLE 8 To a solution of mg. of methanesulfonylchloride in 0.7 ml. of pyridine, there was added 100 mg. of 1 lahydroxyl 0,B-desA-pregnane-5 ,20-dione. The mixture was then allowed to stand overnight at 2 (in a refrigerator), then was diluted with water 100 ml.) and extracted with chloroform (3 X ml.) and methylene chloride (100 ml.). The combined organic extracts were washed with water, 1N hydrochloric acid and again with water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from ether, giving lla-hydroxyl0B-desA-pregnane-5 ,20-dione methanesulfonate, m.p. 139- -l40; [011 46 (c=0.5 in absolute ethanol).

EXAMPLE 9 A solution of 200 mg. of llB-hydroxy-l0B-desA- pregnane-5,20-dione methanesulfonate in 50 ml. of dimethylformamide was refluxed for 8 hours and then evaporated to dryness. The residue was chromatographed on a Florisil (adsorbent) column. Elution with 2 percent ethylacetate/benzene and evaporation of the eluant/yielded desA-pregn-9-ene-5,20dione in the form of colorless needles, mp. l 1 l-l 13. It was shown by mixed melting point to be identical with a sample of the same compound prepared as described in Example 12.

EXAMPLE 10 To a solution of 20 g. of lla-hydroxy-progesterone in 150 ml. of pyridine maintained at 0, there was added 6 ml. of methanesulfonylchloride, and the reaction mixture allowed to stand overnight at 0. it was then diluted with a large excess of water and extracted with chloroform. The organic extracts were washed with 2N hydrochloric acid and water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue was recrystallized from methanol to give l1a-mesyloxy-progesterone, m.p. l59.5l60; [011 +1456 (c=l, chloroform). I

EXAMPLE 1 l A solution of 12 g. of 1la-mesyloxy-progesterone in 300 ml. of methylene chloride/ethyl acetate 2:1) was treated with ozone at -70 until the solution became blue in color. The excess of ozone was removed bybubbling'oxygen through the reaction mixture for 5 minutes. Methylene chloride was then removed under re- I duced pressure, and the solution diluted with ethyl ace and evaporated in vacuo to dryness. The residue crystallized when triturated with ether-acetone mixture, yielding crude lla-mesoxy-S,20-dioxo-3,5-seco-A- nor-pregnan-3-oic acid. After recrystallization from acetone-petroleum ether, m.p. l52153; [01],, a 479 c l, chloroform).

EXAMPLE 12 A solution of 6 g. of l la-mesoxy-5,20-dioxo-3,5- seco-A-nor-pregnan-'3oic acid in 150 ml. of methanol was mixed with a solution of 1.5 g. of sodium carbonate in 55 ml. of water. The mixture was then transferred into a 1 liter sublimation flask, and evaporated to dryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetate is added, and after closing the top part of theapparatus, this mixture was pyrolyzed at 290 and 0.02 mm. for 4 hours. The product, which collects on the cold finger, was dissolved in ether and filtered. The filtrate was then evaporated to dryness. Purification of the residue by chromatography on a 40 g. silicagel column (benzene eluant) gave crystalline desA- pregn-9-ene-5,20-dione; m.p. llll 13 (after recrystallization from ether). [011 56.8 c 0.25 percent in methanol).

EXAMPLE l3 To a solution of 1.2 g. of desA-pregn-9-ene-5,20- dione in 20 ml. of methanol maintained at 0, there was slowly added a cooled solution of 1.2 g. of sodium borohydride in 22 ml. methanol, and the resultant mixture was left for 72 hours at 0. It was then diluted with 100 ml. of water and extracted with four 100 ml. portions of chloroform. The extract was dried over anhydrous sodium sulfate and evaporated in vacuo, yielding a colorless oily product. This product was dissolved in 250 ml. of chloroform and 6 g. of maganese dioxide was added to the solution which was then stirred for 72 hours at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a silica-gel column and the eluates with per cent ethyl acetate in benzene, after concentration gave crystalline 20fl-hydroxy-desA-pregn-9- enS-one which upon recrystallization from methylene chloride-petroleum ether formed colorless needles, mp. 122-l23; (11 -33 (c 0.5, absolute ethanol).

EXAMPLE 14 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of 95 percent ethanol and 5.25 ml. of 2N aqueous sodium hydroxide was hydrogenated at room temperature and atmospheric pressure. To this was added a solution of 262 mg. of 20B-hydroxy-desA-pregn-9-en-5-one in ml. of 95 percent ethanol, and the reaction mixture then hydrogenated at room temperature and atmospheric pressure. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, and the catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. To the residue was added l ml. of glacial acetic acid, and it was then dissolved in 1 liter of ether. The cloudy solution was washed with 2N aqueous sodium carbonate solution, then with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. It yielded a colorless oil, which was chromatographed on a silicagel column using 1 percent ethyl acetate in benzene as the elutant. First eluted was ZOB-hydroxy-lOa-desA- pregnan-S-one, m.p. l07-l08 after recrystallization from methylene chloride/petroleum ether. RD. (in methanol); [011 25.3, [011 [011 274; 1305 1300 Further elution yielded 2OB-hydroxy-9B, lOB-desA- pregnan-5-one as a colorless oil. R. D. (in methanol): 1500 -8 1400 1350 22.2 1310 21480- EXAMPLE 15 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 2 ml. of 3N aqueous hydrochloric acid and 18 ml. of percent ethanol 'was hydrogenated at room temperature and atmospheric pressure. A solution of 262 mg. of ZOB-hydroxy-desA- pregn-9-en-5-one in 5 ml. of absolute ethanol was introduced into the hydrogenation flask, and the reaction mixture was then hydrogenated at room temperature and atmospheric pressure. After one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated by filtration, and the filtrate neutralized with 2N aqueous sodium hydroxide solution. An excess of 5 ml. of 2N aqueous sodium hydroxide was added and the solution allowed to stand overnight. .Ethanol was then removed by evaporation at reduced pressure, and after addition of 1 ml. of glacial acetic acid, it was extracted with 1 liter of ether. The extract was washed with 2N aqueous sodium carbonate solution, then with water, dried and concentrated in vacuo. It gave a colorless oil, which was chromatographed on a silica-gel column using 2 percent ethyl acetate in benzene as the elutant. The first fractions of the eluate yielded, upon concentration, 20B-hydroxy-l0adesA-pregnan-S-one. From the immediately subsequent fraction, 20B-hydroxy-9B, lOfi-desA-pregnan- 5-one was obtained. Both products were identical with the same compounds obtained in Example 14.

EXAMPLE l6 EXAMPLE 17 A medium is prepared of 20 g. of Edamine enzymatic digest of lactalbumin, 3 g. of corn steep liquor and 50 g. of technical dextrose diluted to 1 liter with tap water and adjusted to a pH of 4.3 4.5. Twelve liters of this sterilized medium is inoculated with Rhizopus nigricans minus strain (A.T.C.C. 6227b) with incubated for 24 hours at 28 using a rate of aeration and stirring such that the oxygen uptake is 6.3 7 millimoles per hour per liter of Na SO according to the method of Cooper et al, Ind. Eng. Chem., 36, 504 1944). To this medium containing a 24 hour growth of Rhizopus nigricans minus strain, 6 g. of l7a-acetoxy-progesterone in ml. of acetone is added. The resultant suspension of the steroid in the culture is incubated under the same conditions of temperature and aeration for an additional 24 hour period after which the beer and mycelium are extracted. The mycelium is then filtered, washed twice, each time with a volume of acetone approximately equal in volume to the mycelium, extracted twice, each time with a volume of methylene chloride approximately equal to the volume of the mycelium. The acetone and methylene chloride extracts including solvent are then added to the beer filtrate. The mixed extracts and beer filtrate are then extracted successively with 2 portions of methylene chloride, each portion being one-half the volume of the mixed extracts and beer filtrate, and then with 2 portions of methylene chloride, each portion being one-fourth the volume of the mixed extracts and beer filtrate. The combined methylene chloride extracts are then washed with 2 portions of a 2 percent aqueous solution of sodium bicarbonate, each portion being one-tenth the volume of the combined methylene chloride extracts. The methylene chloride extracts are then dried with about 3 5 g. of anhydrous sodium sulfate per liter of solvent, and then filtered. The solvent is then removed from the filtrate by distillation, and the residue is dissolved in a minimum of methylene chloride, filtered and the solvent evaporated from the filtrate. The resulting crystals are then dried and washed five times, each time witha 5 ml. portion of ether per gram of crystal. The crystals are then recrystallized from ether giving l7a-acetoxyl la-hydroxy-progesterone. l7a-acetoxy-l lot-mesoxyprogesterone is prepared by treatment of l'ia-acetoxy- 1 la-hydroxy-progesterone with 'methanesulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 18 l7a-Acetoxy-5 ,20-dioxo-l la-mesoxy-A-nor-3 ,5-

seco-pregnan-3-oic acid is prepared by ozonolysis of I l7a-acetoxy-l la-mesoxy-progesterone, according to the procedure of Example 11.

EXAMPLE l9 l7a-Acetoxy-desA-pregn-9-ene-5,20-dione is prepared from l7a-acetoxy-5,20-dioxo-1 lamesoxy-A- nor-3,5 seco-pregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12.

' EXAMPLE 20 l7ot-Acetoxy-20B-hydroxy-desA-pregn-9-en-5one is prepared from l7a-acetoxy-desA-pregn-9-en5,20- dione by reduction and reoxidation according to the procedure of Example 13.

EXAMPLE 21 l7a-Acetoxy-20B-hydroxy-9B- IOB-desA-pregnan- 5-one is prepared from l7a-acetoxy-20B-hydroxydesA-pregn-9-en-5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15.

EXAMPLE 22 l7a-Acetoxy-2OB-hydroxy-9B, l a-pregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 17- a-acetoxy-20B hydroxy-9B,1OB-desA-pregnan-S-one according to the procedure of Example except instead of conducting the condensation in absolute ethanol and catalyzing it with sodium ethoxide, the condensation is conducted in acetic acid and is catalyzed with p-toluene sulfonic acid.

EXAMPLE 24 l7B-Hydroxy-5 oxo-3 ,5 seco-A-nor-androstan-3-oic acid is prepared by ozonolysis of testosterone according to the procedure of Example 1.

EXAMPLE 25 17B-Hydroxyl Oa-desA-androstan-S-one and 17,8- hydroxy-IOB-desA androstan-S-one are prepared from l7B-hydroxy-5 oxo-3 ,5 -seco-A-norandrostan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

EXAMPLE 26 l7B-Hydroxy-desA-androst-9en-5 one is prepared from l7B-hydroxy-lOa-desA-androstan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3. Example 26a DesA-androst-9-ene-5,l7-dione is prepared from 17- ,B-hydroxy-desA-androst-9-en-5one by oxidation of the latter with a 2 percent chromic acid solution in percent acetic acid. The so-obtained desA-androst- 9-ene-5,l7-dione is recrystallized from cyclohexane and melts at l23123.5; [M +83 (c 0.1021, dioxane).

EXAMPLE 27 A solution of 236 mg of l7B-hydroxy-desA-androst- 9-en-5-one in 40 ml. percent ethanol and 5.25 ml. 2N aqueous sodium hydroxide solution was hydrogenated with one mole equivalent of hydrogen over 236 mg. of prereduced 5 percent rhodium on alumina catalyst. After separation of catalyst, the solution was concentrated in vacuo to dryness, and the residue taken up in one liter of ether. The ether solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. From the residue 178- hydroxy-9B, 1 OB-desA-androstan-S one was obtained by crystallization. M.p. l44.5-l45; 22 (0 0.103; dioxane). The l7B'acetate (i.e., l7B'acetoxy- 9,8,1OB-desA-androstan-S-one) is obtained by acetylation of testosterone followed by ozonolysis, pyrolysis, bromination and dehydrobromination, and reduction according to the methods of Examples 24, 25, 26 and 27 respectively, and melts at l18-l19; [011 28 to 0.103; dioxane).

EXAMPLE 28 A solution of 238 mg. of l7,Bhydroxy9B,l0B-desA- androstan-S-one, 1 ml. of ethylene glycol and catalytic amountof p-toluene sulfonic acid in ml. of anhydrous benzene was slowly distilled until no more water was coming over. The solution was then concentrated in vacuo to a small volume, and l7B-hydroxy- 9/3,IOBdesA-androstan-S-one S-ethylene ketal was obtained from the residue by crystallization. M.p. l15l 16; [a] 9 (c 0.0987; dioxane).

EXAMPLE 29 To a solution of 282 mg. of l7B-hydroxy-9B,1OB- desA-androstan-S-one S-ethylene ketal ion 50 ml. of methylene chloride was added 1 equivalent of 2 percent chromic acid in pyridine, and the reaction mixture then stirred overnight. The reaction mixture was then washed with percent aqueous sodium hydrogen sulfite, 2N aqueous sodium carbonate, water, then dried over anhydrous sodium sulfate and concentrated in vacuo to dryness. Crystallization of the residue gave 913, lOB-desA-androstane-S l 7-dione S-mono-ethylene ketal. Splitting of the ketal in'acetone solution in the presence of a catalytic amount of p-toluene sulfonic acid gives 9B,IOB-desA-androstane-S,l7-dione which melts, after recrystallization from cyclohexane, at 77.5-78; [a] +55 (c 0.107; dioxane).

EXAMPLE To a preformed solution of one mole equivalent of prop-l '-inyl lithium in 100 ml. of anhydrous liquid ammonia was added tetrahydrofuran solution of 200 mg. of 9B,1OB-desA-androstane-S,17-dione S-monoethylene ketal, and the reaction mixture stirred for 2 hours. After addition of one gram of ammonium chloride, cooling was discontinued, and the reaction mixture allowed to evaporate. The residue was extracted withi methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in 20 ml. of acetone and the catalytic amount of p-toluenesulfonic acid added, and the solution was refluxed for 2 hours, then poured in water and extracted in methylene-chloride. The methylene chloride extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue gave l7a-(prop-l '-inyl)-17,8hydroxy-9B,l0B-desA- androstan-S-one.

EXAMPLE 3 l l7a-( prop-l -inyl)- l 7Bhydroxy-9B, l Oa-androstan- 4-en-3-one is prepared by condensing methyl vinyl ketone with l7a-( prop-l -inyl)-17B-hydroxy-9B,1OB- desA-androstan-S-one according to the procedure of Example 5. The product melts at l64-l65.

EXAMPLE 32 To a stirred solution of one mole equivalent of 2- methylprop-Z-enyl magnesium bromide in 100 ml. of ether at room temperature was added dropwise a solution of 280 mg. of 9B,IOB-desA-androstane-S,l7-dione S-mono-ethylene ketal in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for 1 hour. After cooling in an ice-salt bath, a saturated solution of sodium sulfate was slowly added to decompose the Grignard complex. This was followed by addition of anhydrous sodium sulfate. The solution was'separated by filtration and concentrated in vacuo to dryness. The solution of the residue and of a catalytic amount of ptoluene sulfonic acid in 20 ml. of acetone was refluxed for 2 hours, then poured in water and extracted in.

EXAMPLE 33 l7a-( 2'-methyl-prop-2'-enyl)-17B-hydroxy-9B,l0aandrost-4-en-3-one is prepared from l7a-(2'-methylprop-2-enyl)-17B-hydroxy- 9B,l0a-desA-androstan- 5-one by condensation of the latter with methyl vinyl ketone according to the procedure of Example 5. The product melts at l06108.

EXAMPLE 34 l6a-Acetoxy-20-ethylenedioxy-pregn-4-en-3-one is prepared by acetylation of l6a-hydroxy-20 ethylenedioxy-pregn-4-ene-3,20-dione with one equivalent of acetic anhydride in pyridine solution at room temperature for 2 hours, followed by concentration to dryness in vacuo. l6a-Acetoxy-20 -ethylenedioxy-5- oxo-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of l6a-acetoxy-20-ethylenedioxy-pregn-4- en-3-one according to the procedure of Example l.

EXAMPLE 35 16a-Acetoxy-20ethylenedioxy-lOa-desA-pregnan- 5-one and 16a-acetoxy-20-ethylenedioxy-lOB-desA- pregnan-S-one are prepared from l6a-acetoxy-2O -ethylenedioxy-5-oxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis (according to the procedure of Example 2) and reacetylation with acetic anhydride and pyridine.

EXAMPLE 36 l6a-Acetoxy-20-ethylenedioxy-desA-pregn-9 -en 5-one is prepared from l6a-acetoxy-20-ethylenedioxy- IOa-desA-pregnan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 37 16a-Acetoxy-20-ethylenedioxy-9B, l 0B-desA- pregnan-S-one is prepared from l6a-acetoxy 20- ethylenedioxy-desA-pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

EXAMPLE 38 l6a-Hydroxy-20-ethylenedioxy-9B, lOa-pregn-4-en- 3-one is prepared by condensing l6a-acetoxy-20- ethylenedioxy-desA-9B, 10B-pregnan-5-one with methyl vinyl ketone according to the procedure of Example 5.

EXAMPLE 39 3B-Hydroxy-16a-methyl-pregn-5-en-20-one ethylene ketal is prepared by ketalization of 3B-hydroxy-l6amethyl-pregn-S-en-ZO-one in benzene solution with ethylene .glycol using p-toluenesulfonic acid as catalyst. Pyridine-chromic acid oxidation of the so-obtained 3,8- hydroxy-l6oz-methyl-pregn-5-en-20-one ethylene ketal yields l6a-methyl-20-ethylenedioxy-pregn-4-en-3-one. 16a-methyl-20-ethylenedioxy-5-oxo-3,5-seco-A-norpregnane-3-oic acid is prepared by ozonolysis of 16amethyl-20 -ethylenedioxy-pregn-4-en-3-one according to the procedure of Example 1.

EXAMPLE 40 l6a-methyl-20-ethylenedioxyl Oa-desA-pregnan- -one and 1fia-methyl-ZO-ethylenedioxy- 1 OB-desA- pregnan-S-one are prepared from l6a-methyl-20- ethylenedioxy-5oxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2.

EXAMPLE 41 16a-Methyl-20-ethylenedioxy-desA-pregn-9-en- S-one is prepared from 16oz-methyl-20-ethylenedioxylOa-desA-pregnan-S-one by bromination followed by dehydrobromination, according to the procedure of Example 3.

EXAMPLE 42 l6a-Methyl-20-ethylenedioxy-9B, l OB-desA- pregnan-S-one is prepared from l6a-methyl-20- ethylenedioxy-desA-pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14.

EXAMPLE 43 16a-Methyl-20-ethylenedioxy-9B,10oz-pregn-4-en- 3-one is prepared by condensing l6a-methyl-20- ethylenedioxy-9,8, l OB-desA-pregnan-S -one with methyl vinyl ketone, according to the procedure of Example 5.

EXAMPLE 44 2 l-Acetoxy-l 1or-hydroxy-20-ethylenedioxy-pregn-4- en-3-one is prepared by microbiological treatment of 21-acetoxy-20-ethylenedioxy-pregn-4-en-3-one, according to the procedure of Example 17. 2l-Acetoxyl la-mesoxy-20-ethylenedioxy-pregn-4-en-3-one is prepared by treatment of 21-acetoxy-1la-hydroxy-ZO- ethylenedioxypregn-4-ene-3-one with methanesulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 45 21-Acetoxy-l 1a-mesoxy-ZO-ethylenedioxy-S-oxo- 3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of 21-acetoxy-1 1a-mesoxy-ZO-ethylenedioxypregn-4-en-3-one, according to the procedure of Example 11.

EXAMPLE 46 EXAMPLE 47 2 l-Acetoxy-20-ethylenedioxy9fi,1OB-desA- pregnan-5-one is prepared from 2l-acetoxy-20- ethylenedioxy-desA-pregn-9-en-5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15.

EXAMPLE 48 2 l-Hydroxy-ZO-ethylenedioxy 9l3,10a-pregn-4-en- 3-one is prepared from 21-acetoxy-20-ethylenedioxy- 38 9B,lOB-dsA-pregnan-S-one by condensing the latter with methyl vinyl ketone, according to the procedure of Example 22.

EXAMPLE 49' 1 la-Mesoxy-l604,17a-isopropylidenedioxyprogesterone is prepared by treatment of 1 la-hydroxy- 16a, 1 7oz-isopropylidenedioxy progesterone with methane sulfonyl chloride, according to the procedure of Example 10.

EXAMPLE 50 5 ,20-dioxo-l la-mesoxy-l6a,1 7aisopropylidenedioxy-3,5-seco-A-norpregnan-3-oic acid is prepared by ozonolysis of lla-mesoxy-l6cx,17ozisopropylidenedioxy-progesterone, according to the procedure of Example 1 1.

EXAMPLE 51 1 611,1 7a-isopropylidenedioxy-desA-pregn-9-en- 5,20-dione is prepared from 5,20-dioxo-1 la-mesoxyl6a,17a-isopropylidenedioxy-3,5-seco-A-norpregnan- 3-oic acid by conversion of the latter to its sodium salt, followed by pyrolysis according to the procedure of Example 12.

EXAMPLE 52 20B-Hydroxy-16a,1 7a-isopropylidenedioxy-desA- pregn-9-en-5-one is prepared from 1601,1701- isopropylidenedioxy-desAapregn-9-ene-5,20-dione by reduction and reoxidation, according to the procedure of Example 13.

EXAMPLE 53 ilfi-l lydroxy-lo d,fid isopropylidenedioxy-9B ,1 OB- desA-pregnan-S-one is prepared from 20/3-hydroxyl601,17a-isopropylidenedioxy-desA-pregn-9-en-5-one by hydrogenation according to the procedure of Example 14.

EXAMPLE 54 20B-Hydroxyr16a,l7a-isopropylidenedioxy-9B,10apregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 20B-hydroxy-16a,l7otisopropylidenedioxy-desA-9/3,1OBpregnan-5-one according to the procedure of Example 5.

EXAMPLE 55 711,1 '7a-dimethyll 7B-hydroxy-5-oxo-3 ,S-seco-A- norandrostan-3-oic acid is prepared from 701,17a-dimethyl-testosterone by ozonolysis of the lat ter, according to the procedure of Example 1.

EXAMPLE 56 701,17a-dimethyl-l7B-hydroxy-IlOa-desA-androstan- 5-one and 7a,l7a-dimethyl 17y8-hydroxy-10B-desA- androstan-S-one are prepared from 7a,l7a-dimethyl- 1 7B-hydroxy-5-oxo-3,5seco-A-norandrostan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2. 

1. A PROCESS FOR THE PREPARATION OF A DES A-ANDROST-9-EN5-ONE OF THE FORMULA:
 2. The process of claim 1 wherein the pyrolysis is conducted under alkaline conditions.
 3. A process for the preparation of a desA-pregn-9-en-5-one of the formula:
 4. The process of claim 3 wherein the pyrolysis is conducted under alkaline conditions.
 5. A process for the preparation of a desA-androst-9-en-5-one of the formula:
 6. A process for the preparation of a desA-pregn-9-en-5-one of the formula: 